Delivery of therapeutic compounds directly to affected lung tissues has several advantages. The drug reaches the target tissue without first entering the systemic circulation and being subjected to dilution by the blood, binding to blood components, or metabolism by the liver and excretion by the kidneys. A high local concentration of drug can be achieved in the lungs while the systemic concentration is kept below that likely to cause adverse side effects. In addition, the apical side of the lung tissue—the side exposed directly to inspired air—can be treated with compounds that might not readily cross the endothelium or epithelium, which form barriers between the apical surface and the blood plasma. Similar considerations apply to the tissues lining the nasal passages and sinus cavities.
Several means have been developed to deliver compounds directly to the passages of the lung or nose. The most common form, especially for water-insoluble drugs, is a powder suspension that is propelled into the mouth while the patient inhales. Propulsion is accomplished by use of pressurized gas or by any of a variety of mechanical means of entraining a fine powder into a gas or air stream. Common devices for this purpose include metered dose inhalers (MDIs), turbo inhalers, and dry powder inhalers. Each of these uses a different means of propulsion; however, a common characteristic is that once the therapeutic drug leaves the device it is, or becomes, a fine powder. In an MDI, the drug may be suspended or solubilized in a non-aqueous propellant, which is typically a chlorofluorocarbon or fluorinated hydrocarbon that is a liquid under pressure at room temperature. In turbo inhalers and dry powder inhalers, the drug is present in the form of a micronized powder.
The particle size distribution of the aerosolized drug compositions is very important to the therapeutic efficacy of the drug when delivered by inhalation. Studies of inhaled aerosols indicate that particles or droplets of greater than about 5 micrometers in mean aerodynamic diameter are effectively excluded from entry into the lungs and are captured in the nasal passages or throat and swallowed instead. Thus, the drug compounds delivered by these devices must be formulated in such a way that the mass median aerodynamic diameter (MMAD) is below 5 micrometers. In addition, even smaller particle sizes, on the order of 0.5 to 2.5 micrometers, are needed if the drug is to reach the alveolar sacs deep in the lungs. However, particles with aerodynamic diameter less than about 0.5 micrometers are likely to be exhaled before the drug is totally deposited on the lung surface.
Additional considerations for the use of powder-type drug delivery devices for inhalation include the limited amount of drug that can be contained in one or two puffs from the device and the need for the user to skillfully coordinate hand activation of the device with inhalation. This latter limitation is particularly important for those patients who are disabled, children, or elderly.
Nebulizers offer an alternative method of administering therapeutic agents to the lungs. These devices work by means of an air jet or an ultrasonic pulse that is applied to a solution producing a fine mist. Therapeutic agents dissolved or suspended in the solution can be incorporated into the mist. The patient then breathes the mist in and out over the course of several minutes of treatment, during which 1 to 3 mL of the drug formulation is typically nebulized. Considerations of particle size mentioned above also apply to the droplet size of the mists. However, it is possible to rebreathe a portion of the mist during several minutes of treatment and increase the capture of the fine droplet fraction that can penetrate the lung most deeply. In addition, there is no need for coordination between hand action and breathing, making the nebulizer easier to use for patients. It may be possible, in some cases, to administer drugs not soluble in aqueous solution by nebulizing them in suspension. However, the droplet size of nebulized drug-containing suspensions cannot be smaller than that of the suspended particles. Therefore, the finer droplets produced from these systems would not contain any drug.
Thus, one limitation of nebulized formulations is that they are most suitable for those drug compounds that are sufficiently water soluble such that a therapeutic dose of the drug can be dissolved in from 1 to about 3 mL of aqueous solution. One way around this limitation is to formulate with polar organic solvents or aqueous solutions thereof. However, few organic solvents can be safely inhaled for prolonged periods. Most organic solvents that are currently approved for use in inhalation devices are propellants, such as chlorofluorocarbons (CFCs), which will soon be eliminated from manufacturing for environmental reasons, or the newer hydrofluorocarbons and low boiling hydrocarbons, all of which are expected to evaporate prior to penetrating the lungs. Such solvents can evaporate rapidly during nebulization and leave the drug behind in the device or in large particles that would be likely to be deposited in the mouth or throat rather than be carried to the lungs. Indeed, MDIs were developed to circumvent such problems.
Another way to overcome the solubility problem of the drug is to blend cosolvents such as ethanol, propylene glycol, or polyethylene glycol with water. However, there are limits to acceptable levels of these cosolvents in inhaled products. Typically, the cosolvents make up less than about 35% by weight of the nebulized composition, although it is the total dose of cosolvent as well as its concentration that determines these limits. The limits are set by the propensity of these solvents either to cause local irritation of lung tissue, to form hyperosmotic solutions which would draw fluid into the lungs, and/or to intoxicate the patient. In addition, most potential hydrophobic therapeutic agents are not sufficiently soluble in these cosolvent mixtures.
Thus, there is a need to develop improved systems that can solubilize water-insoluble drugs for nebulization, and to minimize the levels of cosolvent necessary to accomplish this. The ideal system would have a cosolvent concentration below about 15% and in certain cases below about 5%. It would consist of non-toxic ingredients and be stable for long periods of storage at room temperature. When nebulized, it would produce droplets having an MMAD less than about 5 micrometers.
Droplet size considerations are not as critical for sinus or nasal administration, but it is still important to use safe, non-irritating ingredients. An additional consideration for both nasal and inhaled delivery is that some of the formulation will inevitably be tasted and swallowed. Therefore, acceptable taste and odor must be considered important parameters, especially for nebulized formulations where exposure is prolonged and where pediatric subjects form an important fraction of the probable patient population.
Anti-inflammatory corticosteroids, which are essentially water-insoluble drugs that act on inflammatory cells in the respiratory mucosa, are a type of therapeutic compounds in need of improved inhaled delivery. These steroids are useful in treating a variety of inflammatory diseases including asthma.
Asthma is a chronic obstructive disease of the lower airways. The major clinical and pathological features of asthma are (partially) reversible airflow limitations due to bronchial constriction, bronchial hyperreactivity to noxious stimuli such as allergens or cold air, and inflammation of the airways. Anti-inflammatory corticosteroids are useful in treating this last condition. They are the most effective group of therapeutic agents currently available for treating allergic asthma. The steroids suppress many inflammatory processes including inhibition of eosinophilia, epithelial shedding, and edema. The cellular basis of these actions is under active investigation.
Like other steroid hormone analogs, corticosteroids bind with high affinity to cytoplasmic receptor proteins in target cells. The receptor-steroid complexes migrate to the cell nucleus, where they interact with nuclear chromatin to control gene expression. The receptor binding is saturable and very small amounts of steroid suffice to elicit maximum cellular responses, including suppression of inflammation.
Anti-inflammatory steroids can act systemically as well as locally. Therefore, while systemic administration of anti-inflammatory steroids will diminish airway inflammation in asthmatics, it can also cause such adverse effects as general immunosuppression and imbalances in mineral metabolism. The corticosteroids commonly used in asthma treatment have a high ratio of topical to systemic potency. That is, these corticosteroids are highly active when delivered directly to the site of inflammation but relatively inactive when passed through the systemic circulation. The portion of an inhaled dose which is swallowed and absorbed through the intestine or absorbed through the lung tissue into the circulation is subjected to metabolism by the liver and converted to less active compounds with short half-lives. These metabolites are quickly eliminated from the blood, reducing the incidence of systemic side effects.
Among the most commonly used steroids are aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortol, triamcinolone, and others, and their respective pharmaceutically acceptable derivatives, such as beclomethasone diproprionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, triamcinolone acetonide, and others. Fortunately, some of these synthetic steroids have low potentials for systemic absorption because of their unique structures and metabolism.
Corticosteroids have usually been formulated as suspensions of micronized drug powder in chlorofluorocarbon vehicles or with chlorofluorocarbon-free propellants and delivered by metered dose inhaler. The choice of this type of carrier and apparatus was dictated by the fact that corticosteroids are very difficult to stabilize in aqueous media and frequently produce systems that exhibit crystal growth, precipitation, and/or aggregation of suspended or solubilized drug.
Corticosteroids have been formulated in different drug delivery systems for administration to the respiratory tract. U.S. Pat. No. 5,292,499 relates to reverse micelle colloidal dispersions of hydrophilic pharmaceutically active compounds prepared with aerosol CFC propellant formulations useful for topical, endopulmonary, nasal, or inhalation administration.
U.S. Pat. No. 5,208,226 describes the concept of using a novel combination therapy, which has greater efficacy and duration of bronchodilator action than previously known combinations and that permits the establishment of a twice daily dosing regimen. The effective treatment consists of administration of a stimulant bronchodilator, salmeterol, and/or a physiologically acceptable salt thereof, combined with beclomethasone dipropionate in a form suitable for inhalation such as a metered dose inhaler with dry powder or chlorofluorocarbon-containing formulations.
U.S. Pat. No. 5,474,759 discloses aerosol formulations that are substantially free of chlorofluorocarbons, and having particular utility in medicinal applications. The formulations contain a propellant (such as 1,1,1,2,3,3,3-heptafluoropropane), a medium-chain fatty acid propylene glycol diester, a medium-chain triglyceride, optionally a surfactant, and optionally auxiliary agents such as antioxidants, preservatives, buffers, sweeteners and taste masking agents. These formulations are used as carriers for the delivery of inhaled drugs such as albuterol, momestrasone, isoprenaline, disodium cromoglycate, pentamidine, ipratropium bromide, and salts and clathrates thereof.
Recently, several corticosteroid liposomal formulations have been under development. U.S. Pat. No. 5,192,528 discloses the delivery of corticosteroids by inhalation for treating a variety of lung diseases. The carrier consists of an aqueous suspension of sized liposomes containing the drug. This liposome-entrapped drug form is then aerosolized, using a pneumatic nebulizer, to deliver the drug to the lung. Cholesterol and/or cholesterol sulfate can be incorporated into the system to delay the release of corticosteroid from the liposomes in the lung environment. These formulations have many advantages over microcrystalline formulations, including utilization of otherwise water-insoluble materials, sustained pulmonary release, and facilitated intracellular delivery. However, some general problems pertaining to liposomes regarding manufacturing processes, the use of synthetic phopsholipids (such as dilauroylphosphatidylcholine), and the distribution patterns of aerosolized liposomes in the lung may cause difficulties in the wide application of this type of aerosolized formulation.
There are as yet no marketed, commercial liposomal, micellar, or microemulsion formulations available for pulmonary delivery of corticosteroids.